Recovery of sulfamethazine and sulfaguanidine



Sept. 5 1950 H. H. RICHMOND RECOVERY OF' SULFOMETHAZINE AND SULF'AGUANIDNE Filed July 15, 194s @Maffay ifa/'WM /Zf Mm ,MMM/mf ,Www/maf,

Mmm/ranma JM Patented Sept. 5, 1950 RECOVERY OF SULFAMETHAZINE AND SULFAGUANLIDINE Guelph, Ontario, Canada,

Henry H. Richmond,

assignor to United States New 4York, N. Y., a corporation of Rubber Company,

New Jersey Y Application July 15, 1948, Serial No. 38,841

s claims. (o1. 2cm-239.75)

This invention relates to novel improvements in the manufacture of-sulfamethazine and particularly to a simple, inexpensive and efficient method of recovering unreacted sulfaguanidine from the reaction products of the condensation of sulfaguanidine and acetylacetone to form sulfamethazine. Such a reaction mixture comprises sulfamethazine formed inthe reaction, unreacted sulfaguanidine and impurities of unknown na- In addition to providingk a method of reof acetylsulfanilyl chloride with 2-amino-4,6-di-.

methylpyrimidine; However, kpreparation of sulfamethazine by the condensation of sulfaguanidine with acetylacetone has presented the serious disadvantage that the reaction4 mixture con-l tains considerable unreacted sulfaguanidine and there has heretofore been no simple commercially feasible method of recovering this unreacted sulfaguanidine. Since sulfaguanidine is an expensive material, this hasbeen a serious drawback to commercial synthesis of sulfamethazine by this route. `My invention provides a highly satisfactory method of recovering this unreacted sulfaguanidine and thus effects considerable economies in the synthesis of sulfamethazine by the reaction of sulfaguanidine with acetylacetone.

The accompanying drawing, which will be selfexplanatory when considered with the following description, portrays diagrammatically the process of my invention. Optional steps are enclosed in dotted lines.

I have discovered that unreacted sulfaguanidine may be recovered from a mixture of sulfaguanidine, sulfamethazine and impurities which is obtained by the condensation of sulfaguanidine with acetylacetonefto form sulfamethazine in a highly efficacious manner by dissolving the mixture of sulfaguanidine, sulfamethazine and impurities, conveniently in the form of the reaction mixture obtained directly by the condensation,

f temperatures above in dilute aqueous ammonium hydroxide solution with warming, cooling the resulting solution and thereby effecting precipitation 0f the sulfaguanidine, and separating the precipitated sulfaguanidine. My invention is based on the` discovery that by proceeding in this manner a major proportion hy weight of :from 10 to 20 or substantially all of the unreacted sulfaguanidine can be recovered in a form which issubstantially uncontaminated by sulfamethazine. My method is typically carried out by adding a cold dilute aqueous solution of ammonium hydroxide to the reaction mixture, warming the mixture to effect solution of all or. substantially all of the sulfaguanidine `and sulfamethazine, and cooling to eiiectrcrystallization of the sulfaguanidine. The sulfaguanidine is filtered oi and may be re-used for `the preparation of sulfamethazine or for any other useful purpose. g

W hen the foregoing procedure is employed substantially all of the sulfaguanidine present in the mixture is recovered. The dine recovered will depend primarily upon the amount contained in the reaction mixture `and may be as much as 20-30% of the original quantityused.

I have foundV that the use of ammonium hydroxideoffersthe advantage over the use of sodium hydroxide or the like that upon warming sulfaguanidine with sodium hydroxide the sulfaguanidine is decomposed with the evolution of ammonia. Decomposition is particularly rapid at C. However, this is avoided by the present invention since warming with ammonium hydroxide does not have a destructive effect on the sulfaguanidine. Better yields are thusl obtained using ammonium hydroxideand furthermore the productivity of the process is' increased since the mixture can be warmed up more rapidly and to a higher temperature. N

The concentration ofthe dilute aqueous ammonium hydroxide solution used may vary widely. Usually the concentration will not exceed 10% ammonium hydroxide. Generally the strength will'loe within the range of from 1 to 5%.

The amount of the aqueous ammonium hydroxid'e solution employed may vary widely provided it is sufficient to dissolve all of the sulfaguanidine and suliamethazine when the mixture is warmed to a suitable temperature. The temperature to which the mixture is warmed conveniently is within the range of from 50 to 90 C.

I prefer to effect the solution of the sulfaguanidine and the sulfamethazine in the dilute aqueous ammonium hydroxide solution -by warmto a temperature of from 50 to 75 C. and to cool the resulting solution to a temperature of not over 20 C. and preferably to a temperature of C. in order to effect precipitation of the sulfaguanidine. l

When the mixture of sulfaguanidine, sulfaamount of sulfaguanimethazine and impurities is warmed with the aqueous ammonium hydroxide solution, there may be impurities which do not go into solution. I find it desirable to remove such impurities by filteringoi, lthe solution therefrom so that upon cooling the sulfaguanidine which precipitatesis not contaminated with such impurities. still purer grade of sulfaguanidine is desired the sulfaguanidine that crystallizes out upon cooling may be reciystallized from water.

The step of warming the reaction mixture with ammonium hydroxide to eiTect substantially complete solution is advantageous since in this way it is possible to remove a small quantity of impurity that is not soluble in the warm solution. Furthermore the separation of sulfaguanidine from sulfamethazine by the method of my invention is much more eiiicient than the mere leaching out of the sulfamethazine lwith cold ammonium hydroxide.

It was not to be expected that ammonium hydroxide would form a stable salt with sulfamethazine in water at an elevated temperature since ammonium hydroxide is a weak base and sulfamethazine is a weak acid; hence there was astrong probability that the salt Wouldbe hydrolyzed in water on heating. For this reason the use of ammonium hydroxide could not be predicted from the use of sodium hydroxide under the conditions used by me or under the conditions of no heating. l

I have found that when sulfaguanidine is separated in accordance with my invention no sulfamethazine is precipitated therewith. lThis is advantageous because loss of sulfamethazine is avoided.

The sulfaguanidine is separated from the cooled'mixture in any suitable manner, typically by filtration. rlhe residual alkaline solution obtained as the ltrate may be worked up in a number of different ways to recover the sulfamethazine contained therein. I often iind it desirable to treat the alkaline solution with decolorizing activated carbon, preferably in conjunction with sodiumfhydrosulte, at this point in order to obtain sulfamethazine of higher quality. However this step may be omitted if desired.

The solution may then be acidied with any suitable acid, such as sulfuric acid or hydrochloric acid, past the point at which sulfamethazine precipitates to a point at which there is no undissolved material present. The acidii'led solution may then be treated with decolorizing activated carbon, it having been found that different impurities are absorbed by activated carbon from the acidied solution than are absorbed from the alkaline solution. In fact this treatment with decolorizing carbon is more important than the treatment of the alkaline solution with decolorizing carbon. The thus-treated solution may then be processed to recover the sulfamethazine therefrom.

The sulfamethazine is recovered from the acidiedsolution by neutralization with ammonium hydroxide which precipitates the sulfamethazine. For example, the required amount of ammonium hydroxide solution may be added to the acidied solution slowly with eiiicient stirring while maintaining the temperature at not over C., and preferably at from 10 to 20 C. In this way the suliamethazine precipitates in granular form.. If the ammonium hydroxide solution is added too rapidly or if the temperature is not suiiciently low the sulfamethazine precipitates as a gummy Ii a' 4 mass which occludes impurities and is diiicult to handle.

However, a preferred method of recovering the sulfamethazine from the acidied solution, from which the sulfaguanidine has been removed as described above, comprises eiecting the neutralization in two steps, the solution being rst neutralized to a pH of from 1.3 to 2.5, preferably to a pH of from 1.7 to 1.8, which effects precipitation of gummy impurities which can then be removed by decantation. The residual solution is then completely neutralized with ammonium hydroxidetoprecipitate sulfamethazine of high quality. The iinal neutralization accomplishes substantially complete neutralization, giving a mixture having a pH of from 6 to 7. The precipitated sulfamethazine is separated from the resulting slurry in any suitable manner, as by ltration. The method just described gives a sulfamethazine product of higher quality than that obtained by the method described in the preceding paragraph.

The following specific examples .illustrate in greater detail the practice of my invention.

Example 1 A mixture of 20.0 g. (0.0866 mole) of sulfaguanidine and,9.5 ce. (approx. 0.09.27 mole) of commercial acetylacetone was reuxed for seventeen hours, heating with an oil bath kept at C. The reaction mixture was dissolved by warming to 70 C. with a solution of 20 cc. of 28% ammonia and 100 cc. of water and after filtering of the small quantity of insoluble material it was allowed to cool to 20 C. The Iprecipitated sulfaguanidine was ltered off and washed with water, the recovery being 3.6 g. or 18%, M. P. 160 C. -The filtrate was placed in a 500 cc. S-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel. Whilewerming on the steam bath 'with stirring, 35 cc. of 37% hydrochloric acid was added obtaining a clear solution in this manner. The acid solution was then stirred with l g. of decolorizing carbon and liltered. The filtrate was carefully neutralized with ammonia to a pH of 1.7. Ihe amorphous precipitate weighing 0.5 g. that came down was removed and the clear liquid remaining was neutralized to a pH of 6 7. The sulfamethazine that came down at this point was ltered off and washed with water, the yield being 16.5 g. or 84% of theory, M. P. 190 C.-l95 C.

Example 2 To a one litre three-necked, flask equipped with a stirrer, a reux condenser and a thermometer, there was added 400 g. of sulfaguanidine hydrate (1.72 moles) andy cc. of commercial grade acetylacetone (approx. 1.855 moles) which was specied as containing abovev 90% acetylacetone. The mixture was refluxed with stirring, being heated with an oil bath kept at lli-0 for 19 hours. The internal liquid temperature was 97-105". Throughout the rst halfof the reaction period the mixture was in solution but subsequently a solid precipitated.

The reaction mixture was steam distilled until 880 cc. of steam distillate was accumulated. The remaining suspension whose volume was about a litre and which' was close to the boiling temperature was filtered through a steam. jacketed Bchner and washed 'with 200 cc. of boiling water. The crystalline white sulfamethazine that was iiltered ofi weighed 322 g., M. P. The ltrate on cooling deposited a yellowish drop of crystals L covery of 6.8%.

i the yield Vis 89% based f'lhe yield oi sulfamethazine is 95% on the basis lthat the crude mixture of 118.3 g. of sulfaguaniprecipitated 166, Awas ltered ofi and the filtrate was slowly 1 neutralized with cooling to drochloric` acid solution.

famethazine weighed 15.1 g., M. P. 190, a yield ``vvlfii'c'h"wasa mixture of sulfamethazine and suljiaguanidine weighing 118.3'g., M. P. 140-145" "'Ijheaqueous motherliquor whose volume was "1,1170 cc. was evaporated to 'dryness yielding `a gummy solid'weighing 20 g- In order to `determine the proportion of sulfaguanidine and sulfamethazine in the crude mixture obtained'after `the removal of the pure sulfamethazine, the crude mixtureof sulfamethazine and sulfaguanidine was dissolved up with warmfing to 'l0-75 C. in a litre tion containing '75 cc. of

of an ammonia solu- 28% ammonia. On

` cooling a crop of 82 g. of sulfaguanidine was riltered ofl, M. P. 180.

The iiltrate was acidiied removal of syrup was neutrapoor dualityy crude sulfarnethwhich on crystallization from The steam'distillate was analyzed for acetyl- Vacetone by condensation of a l cc. aliquot with f" e-fphenylenediamine,v (Thiele da ,Steimmig Bei-*richte 40, 455 (1907 The weight of black pre-- lcipitate was,1-.72 g'. -indicatingthat there was 12.5 gl of-acetylacetone'inthesteam distillate', a re- The recovery or" suliamethazine was 340 g. which on the sulfaguanidine not recovered.

dine-sulfamethazine recovered, is considered to `be sulfaguanidine'.

' rdmple 3 A mixture of 20.0 g. (r0.094 mol) anhydrous suliaguanidine and 9.5 cc. (approx. 0.095 mole) of commercial acetylacetone was reuxed for sixteen hours; The reaction product was' dissolved in a solution of 20 cc. of concentrated (28%) ammonia in 100 cc. of water with warming to 'T0-75 C. and allowed to cool to room temperature. The sulfaguanidine weighing 4.3 g., M. P.

a pI-lv of 6.2using hy- The precipitated sul- Example 4 A mixture of 15.0 g. (0.065 mole) of sulfaguanidine and 7.1 g. of acetylacetone was refluxed for nineteen hours, heating with an oil bath kept at 170 C. The reaction mixture was dissolved in a solution of 20 cc. of 28% ammonium hydroxide solution in 100 cc. water by warming to 'I0-'75 C. with stirring. The small `quantity of insoluble material (0.2 g.) was iiltered from the warm solution which was then allowed to Icool. The sulfaguanidine that precipitated was filtered ofi and washed with water until the washings were neutral; the weight of sulfaguanidine was 3 g., M. P. 170-185" C., a recovery of 20%. The alkaline iiltrate was acidifled with sulfuric acid solution while stirring and the resulting solution was treated with decolorizing carbon and filtered. The filtrate was then neutralized with ammonium hydroxide to a pI-I of 6-7 while stirring, keeping the temperature at 10-15 C'. The `precipitated sulfamethazine was filtered off and washed with water, the yield being 13 g. or 90% of theory, M. P. 18S-190 C.

of sulfaguanidine was 20% and amethazine could "from sulfamethazine. separation is indicated by the fact that substan- 'Fronrtheforegoing description'it will be seen that the present invention provides a highly advantageous method of' separating sulfaguandine The effectiveness of the 'tiaiiyne sulfamethazine is` 10st with the sulfa- `guanidine and substantially allv of lthe sulfa- `lor the reason that the reactionmixture is not a Ysimple onev 4ofsulaguanidine and sulfamethazine alonebutcontains in addition an unknovm num- .ber of Vunknown impurities; henceit could not be predicted thatthe impurities would not have solubility characteristics similar to those of sulfa- "gu'anidine' in which case upon cooling the hot .ammoniacal extract of the reaction mixture such yimpurities would precipitate with the sulfa- Vgu'anidirie yielding a sulfaguanidine of very poor `duality which would have to be purified by crys- .tallization from organic solvents or other means.

Thesuliaguanidine recovered by the present invention fofgood quality often having a melting pointes high as 170 to 180 C. Vand is usable for themanufacture of sulfamethazine when blended withI fresh suliaguanidine. Alurthernfiore the possibility` of purifying the sulfamethazine by the 1 partial or step-wise neutralization method described above could not have been predicted. In addition it was not to be foreseen that sulfamethazinefcould be obtained `from the crude re- :g action product by the method described in a ypurity satisfactory for use directly for veterinary purpo-ses withoutv further purification as by crystallization which is required when other processes .oii'making suliamethaaine and the other sulfa 'idrug's are employed.

4Having `thus described my invention, what I claim and desire to protect by Letters Patent is:

1'.V A process for the recovery of unreacted sulfaguanidine substantially uncontaminated by sullfam'ethazine ironia mixture of suliaguanidine,

` suliamethazine and impurities,V which mixtureis r obtainedby the condensation of suliaguanidine with a'cetylacetone to form sulfamethazine, which *comprises lheating said mixture with dilute aque- 'tousiiammonium hydroxide solution with warmresulting solution and ing and thereby effecting solution of substantially all of said sulfaguanidine and sulfamethazine, cooling the resulting solution and thereby effecting precipitation of the sulfaguanidine substantially uncontaminated by sulamethazine, and separating the precipitated the cooled mixture.

2. A process for the recovery of unreacted sulfaguanidine substantially uncontaminated by sulfamethazine from a mixture of sulfaguanidine, sulfamethazine and impurities, which mixture is obtained by the condensation of 'sulfaguanidine with acetylacetone to form sufamethazine, which comprises heating said mixture with dilute aqueous ammonium hydroxide solution at a temperature of from 50 to 90 C. and thereby effecting solution of substantially all of said sulfaguanidine and suliamethazine, separating any undissolved impurities from the resulting solution, cooling the thereby effecting precipitation of the suliaguanidine substantially uncontaminated by sulfamethazine, and separating'the sulaguanidine from comprises heating said mixture with dilute aque- ;ous ammonium hydroxide solution at a temperature of from 50 to 75 C. and thereby effecting solution. of substantially all of said sulfaguanidine YEand.suifamethazine, cooling the resulting solu- `ntionito a temperature of from 10 to 20 C. and thereby erlecting precipitation of the sulfa- .guailidine substantially uncontaminated by sulfametliazine, and separating the precipitated sulfaguaiiidine from lthe cooled mixture.

4. A process for the separate recovery of un- Vreacted suliaguanidine substantially uncontaminatedby suli'amethazine and of sulfamethazine from a mixture of sulfaguanidine, sulfamethazine andimpurities, which mixture is obtained by the condensation of sulfaguanidine with acetylacetone to form suliamethazine, which comprises vheating said mixture with dilute aqueous am- ,moniurn hydroxide solution and thereby effecting solution or substantially all of said sulfaguanidine `-and. sulfamethazine, cooling the resulting solution l and thereby eiiecting precipitation of the sulfaguanidine substantially vuncontaminated by sulffamethazine, separating the precipitated sulfaguanidine from the cooled mixture, acidifying the kresidual alkaline solution to a point at which there is, no undissolved material present, and neutraliz- -ingthe resulting solution with ammonium hydroxide to precipitate sulfamethazine.

` `*5. Api'ocess as in claim 4 wherein the alkaline Solution is treated with decolorizing activated carbon and sodium hydrosulfite prior to said acidl fiiying step.

6. A process as in claim 4 wherein the acidied solution is treated with decolorizing Iactivated carbon prior to said neutralizing step to precipilj-tate sulfamethazine.

= and impurities, which mixture is obtained by the -v condensation of sulfaguanidine with acetylacetonev to yform sulfamethazine, Which comprises :heatingsaid mixture with dilute aqueous am- :moniumhydroxide solution and thereby eiecting l solutioniof substantially all of saidsulfaguanidine and Sulfamethazine, cooling the resulting solution and thereby effecting precipitation of the sulfaguanidine substantially Auncontaminated by sulamethazine,'separating the precipitated sulfaguanidine from the cooled mixture, acidifying the residual alkaline solution to a point at which there is no undissolved material present, partially neutralizing the acidii'led solution With ammonium hydroxide to a pH offfrom 1.3 to 21.5 and thereby effecting precipitation of gummy impurities, separating said impurities, and neutralizing the residual solution with ammonium hydroxide to a f pH of from 6 to 7 to precipitate sulfamethazine.

8. A process for the separate recovery of. un-

. reacted sulfaguanidine substantially uncontaminated by sulfamethazine and of sulfamethazine from a mixture of sulfaguanidine, sulfamethazine and impurities, which mixture is obtained by the condensation of sulfaguanidine with acetylacetone to form sulfamethazine, which comprises heating said mixture with dilute aqueous ammonium hydroxide solution and thereby effecting solution of substantially all ofsaid sulfaguanidine and sulfamethazine, cooling the resulting solution and lthereby eiecting precipitation of the sulfaguanidmine substantially uncontaminated by sulamethazine, separating the precipitated sulfaguanidine from the cooled mixture, acidifying the residual alkaline solution to a point at which there is no undissolved material present, treating the acidiiied solution with decolorizing activated carbon, and neutralizing the resulting treated solution With ammonium hydroxide While agitating and maintaining the mixture at a temperature at from 10 to 20 C. and thereby precipitating sulfamethazine.

' HENRY I-I. RICHMOND.

REFERENCES CITED The following references are of record in the le o'this patent:

UNITED STATES PATENTS Number Name Date 2,309,739 Roblin et al Feb. 2, 1943 2,392,125 Dhein Jan. 1, 1946 2,407,966 Sprague i Sept. 17, 1946 2,417,939 Kuh et al. f Mar. 25, 1947 2,420,703 Ellingson May 20, 1947 

1. A PROCESS FOR THE RECOVERY OF UNREACTED SULFAGUANIDINE SUBSTANTIALLY UNCONTAMINATED BY SULFAMETHAZINE FROM A MIXTURE OF SULFAGUANIDINE, SULFAMETHAZINE AND IMPURITIES, WHICH MIXTURE IS OBTAINED BY THE CONDENSATION OF SULFAGUANIDINE WITH ACETYLACETONE TO FORM SULFAMETHAZINE, WHICH COMRPISES HEATING SAID MIXTURE WITH DILUTE AQUEOUS AMMONIUM HYDROXIDE SOLUTION WITH WARMING AND THEREBY EFFECTING SOLUTION OF SUBSTANTIALLY ALL OF SAID SULFAGUANIDINE AND SULFAMETHAZINE, COOLING THE RESULTING SOLUTION AND THEREBY EFFECTING PRECIPITATION OF THE SULFAGUANIDINE SUBSTANTIALLY UNCONTAMINATED BY SULFAMETHAZINE, AND SEPARATING THE PRECIPITATED SULFAGUANIDINE FROM THE COOLED MIXTURE. 